The demand for enantiomerically pure compounds has grown rapidly in recent years. One important use for such chiral, non-racemic compounds is as intermediates for synthesis in the pharmaceutical industry. For instance, it has become increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. These advantages (reviewed in, e.g., Stinson, S. C., Chem Eng News, Sep. 28, 1992, pp. 46-79) include the fewer side effects and greater potency often associated with enantiomerically pure compounds.
Traditional methods of organic synthesis were often optimized for the production of racemic materials. The production of enantiomerically pure material has historically been achieved in one of two ways: use of enantiomerically pure starting materials derived from natural sources (the so-called “chiral pool”); and the resolution of racemic mixtures by classical techniques. Each of these methods has serious drawbacks, however. The chiral pool is limited to compounds found in nature, so only certain structures and configurations are readily available. Resolution of racemates, which requires the use of resolving agents, may be inconvenient and time-consuming.
One method of obtaining enantiomerically pure materials is by enantioselective alcoholysis of meso, prochiral, and racemic cyclic anhydrides (EACA). These reactions appear to be broadly applicable to both research and industrial scale a symmetric synthesis of a wide variety of important chiral building blocks, such as hemiester, α-amino acids and α-hydroxy acids. Commercially available modified dimeric cinchona alkaloids (DHQD)2AQN, (DHQ)2AQN, have been identified recently by Deng and coworkers as enantioselective and recyclable catalysts for enantioselective alcoholyses of cyclic anhydrides. However, commercially available (DHQD)2AQN is expensive. For example, the commercial price (Aldrich Chemical Company) for a mole of (DHQD)2AQN is more than $100,000.00. Furthermore, the dimeric catalyst is not available in large quantity (e.g., in kilogram quantity). Therefore, the stereoselective alcoholysis of cyclic anhydrides using dimeric catalysts is not practical on a relatively large scale (>0.1 mol). Consequently, the development of a new generation of monomeric catalysts that is comparably effective to (DHQD)2AQN, but substantially less costly to produce, is of significant practical value. Remarkably, we have developed such monomeric catalysts for asymmetric alcoholysis of cyclic anhydrides.